Here, R-115, an oncolytic herpes simplex virus retargeted to human erbB-2, fully virulent in its target cells, and armed with murine interleukin-12 was evaluated in a murine model of glioblastoma.
We then outline preclinical approaches that employ CAR-NK cells for GB immunotherapy, and give an overview on the ongoing clinical development of ErbB2 (HER2)-specific CAR-NK cells currently applied in a phase I clinical trial in glioblastoma patients.
ErbB2 Receptor Tyrosine Kinase 4 (ERBB4) is expressed throughout normal brain and is an oncogene in several pediatric brain cancers; therefore, we investigated ERBB4 as a prognostic marker and therapeutic target in GBM.
A total of 17 patients (8 females and 9 males; 10 patients ≥18 years [median age, 60 years; range, 30-69 years] and 7 patients <18 years [median age, 14 years; range, 10-17 years]) with progressive HER2-positive glioblastoma received 1 or more infusions of autologous HER2-CAR VSTs (1 × 106/m2 to 1 × 108/m2) without prior lymphodepletion.
High serum EGFR and ErbB2 levels were associated with risk of developing glioblastoma (P = 0.008; OR = 1.58, 95 % CI = 1.13-2.22 and P = 0.017, OR = 1.63, 95 % CI = 1.09-2.44, respectively).
Subsequent pathway analysis of the lncRNA-paired genes indicated that EphrinB-EPHB, p75-mediated signaling, TNFα/NF-κB, and ErbB2/ErbB3 signaling pathways might be altered in glioblastoma.
Moreover, multi-factor regulations especially the key regulation subtypes may be more relevant to GBM and affect many GBM-related genes such as ERBB2 and MAPK1.
The specificity of the tagged NPs was determined by studying their effect relative to that of non-tagged NPs against two cell lines: human adenocarcinoma SK-BR3, overexpressing the HER2 receptor; and U-87 MG, a human glioblastoma epithelial cell line, not expressing HER2.
We observed that targeting HER2 in a glioblastoma (GBM) cell line results in the emergence of HER2-null tumor cells that maintain the expression of nontargeted tumor-associated antigens.
Dual inhibition of EGFR and ERBB2 with lapatinib significantly reduced GBM proliferation in colony formation assays compared to cetuximab-mediated EGFR-specific inhibition.
We report on the safety and efficacy in a high-grade glioma (HGG) model of R-LM113, an HSV recombinant retargeted to human epidermal growth factor receptor 2 (HER2), frequently expressed in GBMs.
We have shown that miRNA-7 (miR-7) and miRNA-331-3p (miR-331-3p) directly regulate expression of EGFR and HER2, respectively, in glioblastoma and prostate cancer cell lines.
The strongest c-erbB-2 immunoexpression was observed in low grade astrocytomas (diffuse astrocytomas G2); in the glioblastoma group the c-erbB-2 protein expression was weak and 17.4% of cases were negative.
Our findings with immunohistochemistry and western blot analysis indicate a level of ErbB-1 similar to normal peripheral nerve, but a high expression of ErbB-2 similar to the vestibular schwannoma and glioblastoma multiforme.
We undertook a phase I/II study of the EGFR/erbB2 inhibitor lapatinib in patients with recurrent glioblastoma multiforme (GBM) to determine response rate, pharmacokinetics (PK) and recommended dose in patients taking enzyme-inducing anti-epileptic drugs (EIAEDs) and to explore relationships of molecular genetics to outcome.
This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol-3-OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma.
To assess the dependence of EGFR inhibited phenotype on p53, we used three mutant p53 glioblastoma cell lines in the present study and showed that mutant erbB2 can be exploited to inhibit EGFR-mediated oncogenic transformation irrespective of p53 status.
Our data from immunohistochemistry indicate that ERBB2 expression in GBM is closely correlated with EGF receptor levels and is therefore not useful as an independent prognostic parameter.
The specificity of the elevated transcription of TGF-alpha, TGF-beta, bFGF and flg in glioblastoma cell lines is further suggested by the fact that the transcription of the proto-oncogene c-erbB2, which is overproduced in breast tumor cell lines, was not elevated in glioblastoma cell lines.
The neu gene in rat neuro/glioblastoma was found to be activated by a single point mutation in the DNA sequence encoding the transmembrane region of the neu-encoded p185 protein.